Polycystic ovary syndrome (PCOS) is one of the most common human reproductive endocrine disorders. PCOS is not only a gynecological condition presenting with symptoms such as hirsutism, infertility, recurrent pregnancy loss and endometrial carcinoma, but a comprehensive syndrome with a variety of associated metabolic disorders. Recent recognition of the prominent role of insulin resistance in PCOS has emphasized the metabolic aspects of the disorder and highlighted the associated risks of type II diabetes mellitus (DM) and cardiovascular disease (CVD). The reproductive and metabolic morbidities of PCOS make it an important women's health issue, with medical consequences across the lifespan of affected individuals. However, the etiology and pathogenesis of the syndrome are unclear, and there is no effective cure. Currently, no comparative animal model of PCOS exists that fully embodies the complexity of the syndrome. The objective of this application is to characterize and validate the female Ossabaw pig as a model of PCOS that embodies both the metabolic and reproductive aspects of the syndrome. We hypothesize that the Ossabaw pig is a good comparative animal model of both the metabolic and reproductive mechanisms of PCOS based upon our strong preliminary findings, which demonstrate that female Ossabaw swine naturally develop many characteristics of metabolic syndrome (MS) when fed in excess, and that they develop features of PCOS with MS, namely hyperandrogenemia, enlarged ovaries and altered follicular growth. We plan to accomplish our objective by pursuing a single Specific Aim: Evaluate specific reproductive and metabolic etiologies of PCOS in Ossabaw females fed a diet that induces metabolic syndrome. Reproductively, these include hyperandrogenemia, abnormal theca cell androgen production, altered LH:FSH ratios, cystic ovaries and anovulation. Metabolic parameters include dyslipidemia, glucose intolerance, hyperinsulinemia, and specific alterations in insulin receptor signaling. This team is particularly well prepared to undertake the proposed research, as they have combined expertise in the areas of reproduction, endocrinology, cardiovascular disease and adiposity. The proposed research is innovative in that it will characterize, for the first time, a model for PCOS in which the complex abnormalities of the syndrome can be studied as a whole. The rationale for the proposed research is that characterization of the Ossabaw mini-pig as a model of PCOS will permit significant advances in the field. Researchers will be able to elucidate the pathophysiology of the disease and thus develop management strategies for the immediate symptoms of PCOS, such as infertility, androgen excess and metabolic syndrome, as well as its long term health implications, including endometrial cancer, diabetes and cardiovascular disease. PUBLIC HEALTH RELEVANCE: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive aged women. Currently, there is no complete animal model that represents both the reproductive and metabolic complexities of the syndrome. Characterization of the Ossabaw mini-pig as a model of PCOS will permit significant advances in the field. Researchers will be able to elucidate the pathophysiology of the disease and thus develop management strategies for the immediate symptoms of PCOS, such as infertility, androgen excess and metabolic syndrome, as well as its long term health implications, including endometrial cancer, diabetes and cardiovascular disease.